Our work is dedicated to the better understanding of common molecular and cellular mechanisms of neurodegeneration, with the ultimate goal of developing treatments for neurodegenerative diseases and even preventing them. The lab currently focuses on investigating an evolutionarily conserved neuronal stress response pathway under control of DLK (dual leucine zipper kinase), which plays an important role in several neuropathologies. As a cellular stress response pathway in neurons, its function is to promote recovery from injury; however, at the same time, it can drive several types of pathologies, including peripheral neuropathies and neurodegeneration. The hypothesis driving our work is that common mechanisms are responsible for neurodegeneration during development, childhood, and aging. Most of what is currently understood about neurodegenerative disease stems from the identification of genetic linkages that are causative or predisposing, and from efforts to uncover the mechanisms underlying these linkages. However, the linkages only account for a relatively small proportion of all cases. The vast majority of cases have no established genetic etiology and therefore no clear pathway to target. An understanding of any common mechanisms involved in neurodegeneration would provide major breakthroughs for designing treatments. We showed that Dual Leucine Zipper Kinase (DLK; MAP3K12) acts as a crucial downstream node in neurodegeneration and neuropathy, two pathologies with very different causes and outcomes (Le Pichon et al., 2017; Wlaschin et al., 2018). The lab is currently investigating how such diverse diseases converge upon this single pathway and how this pathway mediates divergent fates. The DLK-dependent injury response promotes neurodegeneration in the mammalian CNS. The existence of common mechanisms of neurodegeneration has long been hypothesized. In previous work, I focused on DLK, which is a MAP3 kinase (mitogen activated protein triple kinase) previously shown to initiate a retrograde stress signaling cascade from the axon to the cell body, and which has since become a promising drug target for the treatment of several diseases. As a kinase that is enriched in neurons, DLK is an attractive drug target and was identified in several screens for genes that drive neurodegeneration. Moreover, DLK is upstream of JNK (c-Jun N-terminal kinase) signaling, which itself has long been proposed as a therapeutic target for neurodegeneration, but whose specific targeting has not proved feasible. Importantly, the work uncovered a powerful role for DLK signaling in several animal models of neurodegeneration and showed that human disease tissue bears markers of DLK/JNK signaling activation (Le Pichon et al., 2017). The most exciting implication of this study is that DLK is an important driver of neurodegeneration with diverse etiologies, suggesting it is part of a long sought common mechanism of neurodegeneration and is thus an attractive therapeutic target. Intriguingly, and at first glance perhaps counter-intuitively, DLK signaling can result in many different outcomes, including neuronal death and long-term survival, depending on context. Several studies have shown that DLK can promote neuron death in the CNS (central nervous system), for example after injury to the optic nerve, and during normal development. However, DLK is also described as an important pathway for axon regeneration after neuron injury. Therefore, it is thought of as a regulator and coordinator of neuronal stress signaling, able to promote recovery or death. My lab is now focusing, in parallel, on two key questions: understanding how DLK performs these dual roles; and determining how distinct diseases converge upon this common pathway. DLK is required for microgliosis and pain after traumatic injury to sensory neurons. In recent work, we have investigated a potential role for DLK in pain. It was clear that peripheral nerve injury activates many molecules downstream of DLK. However, the possibility of links between injury, DLK, and neuropathic pain had not been examined. Notably, work in my lab established that DLK signaling plays a causative role in chronic neuropathic pain after nerve injury, raising the possibility that inhibition of DLK would also be an effective treatment for pain (Wlaschin et al., 2018). Partial sciatic nerve axotomy results in the development of mechanical hypersensitivity (allodynia), which can be measured by a reflexive paw withdrawal response. We demonstrated that DLK deletion or inhibition blocks the development of this mechanical allodynia by preventing the full complement of transcriptional changes that normally occur following injury. Strikingly, we discovered a novel role for DLK in regulating a microglial reaction in the vicinity of injured neurons. DLK controls a distress call from injured neurons to microglia via transcriptional upregulation of the neuronal cytokine Csf1, resulting in a characteristic spinal cord microgliosis at the central terminals of the DRG neurons. The microgliosis is blocked in the DLK conditional knockout (DLK cKO). Our data corroborate recent work from others showing that neuronal expression of Csf1 after injury is required for the spinal cord microgliosis and necessary for the development of the mechanical allodynia (Guan et al., Nat Neurosci 2016;19:94). Our results expose DLK as a critical regulator of events leading from nerve injury to the development of neuropathic pain and suggest that targeting this pathway might be of therapeutic value. They also highlight non-cell autonomous aspects of the neuronal injury response, for example an injured neuron-to-microglia signal that has important implications in the context of neurodegeneration, and in which neuroinflammation is thought to be a key player. Understanding differential responses downstream of DLK Because DLK activation in a neuron can counterintuitively lead both to degeneration and cell death as well as regenerative responses, current efforts aim to better understand these differential downstream signaling arms. A better understanding of what controls the beneficial versus detrimental aspects of the nerve injury response could lead therapies in which degeneration is inhibited while regeneration is promoted. Dissociating these responses would get around the problem that by inhibiting DLK we are also blocking desired adaptive/regenerative responses. This could be a powerful therapeutic strategy both for neurodegenerative diseases as well as painful neuropathies.